Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain

Abstract

Cognitive decline is a common pathological outcome during aging, with an ill‐defined molecular and cellular basis. In recent years, the concept of inflammaging, defined as a low‐grade inflammation increasing with age, has emerged. Infiltrating T cells accumulate in the brain with age and may contribute to the amplification of inflammatory cascades and disruptions to the neurogenic niche observed with age. Recently, a small resident population of regulatory T cells has been identified in the brain, and the capacity of IL2‐mediated expansion of this population to counter neuroinflammatory disease has been demonstrated. Here, we test a brain‐specific IL2 delivery system for the prevention of neurological decline in aging mice. We identify the molecular hallmarks of aging in the brain glial compartments and identify partial restoration of this signature through IL2 treatment. At a behavioral level, brain IL2 delivery prevented the age‐induced defect in spatial learning, without improving the general decline in motor skill or arousal. These results identify immune modulation as a potential path to preserving cognitive function for healthy aging. image Delivery of interleukin 2 into the brain via a blood–brain barrier crossing AAV vector prevents cognitive decline in the aging mice. A gene delivery system uses an AAV‐based viral vector coupled with an astrocyte‐specific promoter to drive the expression of the anti‐inflammatory cytokine interleukin 2 in the brain of aged mice. At a molecular level, brain‐specific expression of IL2 in aged mice partially reverted the transcriptional signature of aged glial cells to the baseline state of young glial cells. At a cognitive level, brain‐specific expression of IL2 in aged mice partially restored the spatial learning decline, without improving the general decline in motor skill or arousal.